In the field of obstetrics, one of the most important problems is the management of preterm labor and premature birth as they represent a major cause of perinatal morbidity and mortality.
For the treatment of preterm labor the use of magnesium sulfate and ethanol has been suggested. However, magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable notably when the renal function is impaired.
Ethanol is effective in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress. Also, ethanol is assumed to have a negative impact on the fetus.
Two further therapeutical agents fall into either of the groups of:                a) β2-adrenergic agonists, or        b) oxytocin antagonists.        
The β2-adrenergic receptor generally causes an inhibitory action within the cells wherein it is expressed (muscles, heart, uterus etc). β2-adrenergic agonists are used to activate said inhibitory action of the receptor. Hence, β2-adrenergic agonists are sympathomimetics which—among others—inhibit uterine contractility. Known β2-adrenergic agonists for the treatment of preterm labor are Ritodrine, Tetbutaline and Albuterol.
Ritodrine (i.e. (R*,S*)-4-Hydroxy-.alpha.-[1-[[2-(4-hydroxyphenyl)ethyl]amino]ethyl]-benzenemethanol; see U.S. Pat. No. 3,410,944 of N. V. Philips) is the leading β2-adrenergic agonist but causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant).
Terbutaline (i.e. 5-[2-[(1,1-Dimethylethyl)amino]-1-hydroxyethyl]-1,3-benzenediol, see U.S. Pat. No. 3,937,838, Draco) and Albuterol (α1-[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol; U.S. Pat. No. 3,644,353, Allen and Hanburys) are further β2 -adrenergic agonists and have side effects similar to those of Ritodrine.
A more recent approach of treating preterm labor consists in the use of oxytocin antagonists.
Oxytocin (OT) is a cyclic nona-peptide whose actions are mediated by activation of specific G protein-coupled receptors currently classified into OT receptors (OT-R) (1).
Oxytocin (OT) causes the contraction of the uterus of mammals during labor. The corresponding oxytocin receptor belongs to the family of G-protein-coupled receptors and is similar to V1 and V2 vasopressin receptors. OT receptors increase dramatically during the course of pregnancy. The concentration of OT receptors has been shown to correlate with spontaneous uterine activity (2-3). OT-induced contractions of the uterus during labor result in the dilatation of the cervix and eventually in the movement of the foetus through the vaginal canal. In some cases, these contractions occur before the foetus is fully viable, resulting in premature labor. Premature labor and premature birth are undesired as they are major causes of perinatal morbidity. Hence, the management of preterm labor represents a significant problem in the field of obstetrics.
In recent years, strong evidence has accumulated indicating that the hormone oxytocin plays a major role in initiating labor in mammals, in particular in humans. Thereby, it is assumed that oxytocin exerts said effect in a direct as well as an indirect way, by contracting the uterine myometrium and by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. These prostaglandins may furthermore play a role in the cervical ripening process. This “up-regulation” of oxytocin receptors and increased uterine sensitivity seems to be due to trophic effects of rising plasma levels of estrogen towards term. By down-regulating oxytocin, it is expected that both the direct (contractile) and indirect (increased prostaglandin synthesis) effects of oxytocin on the uterus could be blocked. An oxytocin modulator, e.g. blocker or antagonist would likely be efficacious for treating preterm labor.
A further condition related to oxytocin is dysmenorrhea, which is characterised by pain or discomfort associated with menses. The pain is believed to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By blocking both the indirect and direct effects of oxytocin on the uterus, an oxytocin antagonist would be a likely candidate for treating dysmenorrhea Some agents counteracting the action of oxytocin are currently used in clinical studies (4).
Atosiban, a peptide OT antagonist which is already on the market, suffers the problem of most peptides: low oral bioavail-ability resulting from intestinal degradation. Such compounds must be administered parenterally.
The development of non-peptide ligands for peptide hormone receptors is expected to overcome this problem. Small molecule selective oxytocin antagonists have been reported by Merck. In addition to cyclic hexapeptides, Merck suggested indanylpiperidines and tolyl-piperazines as orally deliverable OT antagonists (5). In WO 96/22775 and U.S. Pat. No. 5,756,497, Merck reported benzoxazinylpiperidines or benzoxainones as OT receptor antagonists.
Specific sulfonamides have been reported to antagonize ocytocin at the ocytocin receptor. Elf Sanofi's EP-A-0469984 and EP-A-0526348 report N-sulfonyl indolines acting as antagonists of the vasopressin and the oxytocin receptors.
American Cyanamid's U.S. Pat. No. 5,889,001 claims pyrazole benzodiazepine derivatives as vasopressin and oxytocin antagonists.
The OT antagonists disclosed in WO 01/72705, WO 02/074741 and WO 02/102799 (Applied Research Systems ARS Holding) arc pyrrolidine-typo compounds.